The goal of our program is to develop novel, nontoxic approaches to cancer intervention with a prime focus on Modulators of Lipid Metabolism. The efficacy of aromatic fatty acids, used alone or in combination with other treatments, was investigated. Studies of mechanisms of action included: (a) inhibition of protein prenylation; (b) activation of the nuclear steroid receptor, PPAR, and of specific transcriptional response elements; (c) DNA methylation. Several clinical trials have been initiated based on our preclinical findings: (a) Phenylacetate phase II in adults with high-grade glioma (UCSF); hormone-refractory prostate cancer (NAVY-NCI); B-cell lymphoma (Mayo Clinic), and melanoma (NCI, Frederick) (b) Phenylacetate phase I, pediatrics (NCI) (c) Phenylbutyrate phase I (CPB-NCI, Johns Hopkins, SKCC) (d) DAC phase II. B-cell lymphoma (Johns Hopkins); renal ca. (Surgery, NCI); prostate ca. (CPB-NCI) (e) Lovastatin in combination with radiation, phase I (UVA) The preliminary findings indicate that phenylacetate is active against CLL and low-grade lymphomas (Mayo) as well as high-grade gliomas (UCSF, CPB), with no significant side effects. --- We plan to expand upon these studies in the hope to further the development of safe and effective approaches to cancer therapy.